Efficient functioning of the immune system requires a fine balance between cell proliferation and differentiation and cell death, to ensure that the immune system is capable of reacting to foreign, but not self antigens. Central tolerance refers to the mechanisms which lead to positive and negative selection of T cells in the thymus where T cells are positively or negatively selected depending on their capacity to interact with self MHC antigens expressed in the thymus. In the periphery, mature T cells which interact with self antigens expressed uniquely in the periphery are deleted, as are T cells which have been activated by foreign antigen. This is known as peripheral tolerance.
Deletion of inappropriately activated T cells is believed to occur via programmed cell death known as apoptosis, which is distinct from cell death due to necrosis. Two members of the TNF family, Fas ligand (FasL) and TNF, have been reported to be involved in some of the effector mechanisms which control immune tolerance (reviewed in Cleveland and Ihle, Cell 81:479; 1995). FasL and TNF mediate their biological effects by binding their respective receptors, which are members of the TNFR superfamily (Smith et al., Cell 76:959; 1994).
Fas (the receptor for FasL) and TNF receptor type I (TNFRI) both contain a unique motif within their cytoplasmic regions, which has been termed the death domain (Tartaglia et al., Cell 74:845, 1993; Itoh and Nagata, J. Biol. Chem. 268:10932, 1993). Overexpression of the death domain in transient transfection systems has been shown to result in apoptosis. The biological effects of Fas/FasL and TNF/TNFRI interactions are thought to occur through both distinct and similar signaling pathways (Schultze-Osthoff et al., EMBO J. 13:4587, 1994; Wong and Goeddel, J. Immunol. 152:1751, 1994).
The lpr and gld mouse models have implicated the Fas/FasL system in peripheral tolerance; however, peripheral T cell deletion does occur in lpr mice. This Fas-independent apoptosis of mature T cells has been shown to be partly TNF mediated (Zheng et al., Nature 377:348, 1995) These data imply that multiple apoptotic mechanisms, including unrecognized ones, may be involved in peripheral tolerance. Moreover, the mechanisms mediating central tolerance remain unknown. Investigation into the existence and identity of other molecule(s) that play a role in apoptosis is desirable. Identifying such molecules would provide an additional means of regulating apoptosis, as well as providing further insight into the development of self-tolerance by the immune system and the etiology of autoimmune diseases.